Malaria, a parasitic mosquito-borne disease, is a major concern worldwide, with 219 million cases occurring in 2017 (WHO 2018 report), causing 435,000 deaths of which 61% were children under 5. Plasmodium falciparum is the causative agent of the deadliest form of malaria and current treatment guidelines include artemisinin-based combination therapies (ACTs), combining one artemisinin derivative (artemether, artesunate or dihydroartemisinin) with one or two different drugs. Most studies have demonstrated that ACTs remain effective, but partial resistance has been reported in southeast Asia, linked to the development of the parasite?s ability to remain dormant at the ring stage long enough for clearance of artemisinin-based drugs so the parasites can re-emerge. Virtually all derivatives of artemisinin currently available are the result of chemical modifications at ?C-10?, or carbon number 10 on its structure (IUPAC numbering). The fungus Cunninghamella elegans can add a hydroxyl group to carbon number 7 (C7) which, until the use of fungal transformation, was inaccessible except through extensive and costly total synthesis. The overall objective for this application is to 1) prepare C-7 derivatives of artemisinin linked with hydrophilic groups and fluorescent probes; 2) test those derivatives against a) standard P. falciparum strains (3D7, W2mef, HB3); b) at least one artemisinin-resistant phenotype (C2A) and c) test for possible anti-gametocyte action and transmission blocking activity by Standard Membrane-Feeding Assay; 3) chemogenomic profiling studies of P. falciparum piggyBac single insertion mutants seeking better understanding of the interaction of these new C7 derivatives of artemisinin with druggable targets and pathways. The central hypothesis is that derivatives of artemisinin without any steric hindrance to the peroxide group will allow full interaction with cellular targets, precisely tagging cellular structures bound to the artemisinin scaffold and enhancing inhibitory effect. These new semi-synthetic derivatives of artemisinin, built for the first time using functional groups placed structurally on the opposite side of the peroxide bridge, are expected to have enhanced antimalarial activity, present better pharmacokinetic profiles and work better as molecular probes for elucidation of mechanisms of action and drug resistance.